Cortico-striatal connectivity and cognition in normal aging: a combined DTI and resting state fMRI study

Resting state fMRI studies have found that cognitive decline in aging is associated with alterations in functional connectivity of distributed neural systems in the brain. While functional connections have been shown to rely on the underlying structural connectivity, direct structural connections have been studied in only a few distributed cortical systems so far. It is well known that subcortical nuclei have structural connections to the entire cortex. We hypothesized that structural subcortico-cortical connections may provide integral routes for communication between cortical resting state networks, and that changes in the integrity of these connections have a role in cognitive aging. We combined anatomical MRI, diffusion tensor MRI, and resting state fMRI in 100 healthy elderly to identify fiber bundles connecting cortical resting state networks to subcortical nuclei. In identified tracts, white matter fiber bundle integrity measures were compared to composite cognitive measures on executive function, processing speed, and memory performance. The integrity (FA values) in selected fiber bundles correlated strongly with cognitive measures on executive function and processing speed. Correlation was most pronounced between executive function and fiber bundles connecting the putamen to the dorsal attention network (r=0.73, p<0.001). Our findings show that unique cortico-subcortical fiber bundles can be identified for a range of cortical resting state networks, and indicate that these connections play an important role in cortical resting state network communication and cognition.     

Loss of Perivascular Kir4.1 Potassium Channels in the Sclerotic Hippocampus of Patients With Mesial Temporal Lobe Epilepsy

ABSTRACT: Recent experimental data in mice have shown that the inwardly rectifying K channel Kir4.1 mediates K spatial buffering in the hippocampus. Here we used immunohistochemistry to examine the distribution of Kir4.1 in hippocampi from patients with medication-refractory temporal lobe epilepsy. The selectivity of the antibody was confirmed in mice with a glial conditional deletion of the gene encoding Kir4.1. These mice showed a complete loss of labeled cells, indicating that Kir4.1 is restricted to glia. In human cases, Kir4.1 immunoreactivity observed in cells morphologically consistent with astrocytes was significantly reduced in 12 patients with hippocampal sclerosis versus 11 patients without sclerosis and 4 normal autopsy controls. Loss of astrocytic Kir4.1 immunoreactivity was most pronounced around vessels and was restricted to gliotic areas. Loss of Kir4.1 expression was associated with loss of dystrophin and α-syntrophin, but not with loss of β-dystroglycan, suggesting partial disruption of the dystrophin-associated protein complex. The changes identified in patients with hippocampal sclerosis likely interfere with K homeostasis and may contribute to the epileptogenicity of the sclerotic hippocampus.     

Screening of FDA-Approved Drugs Using a MERS-CoV Clinical Isolate from South Korea Identifies Potential Therapeutic Options for COVID-19

Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI > 100), atovaquone, an anti-malarial (TI > 34), and ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.     

Anthropomorphic liver phantom with flow for multimodal image-guided liver therapy research and training

Purpose

The objective of this study was to develop a multimodal, permanent liver phantom displaying functional vasculature and common pathologies, for teaching, training and equipment development in laparoscopic ultrasound and navigation.

Methods

Molten wax was injected simultaneously into the portal and hepatic veins of a human liver. Upon solidification of the wax, the surrounding liver tissue was dissolved, leaving a cast of the vessels. A connection was established between the two vascular trees by manually manipulating the wax. The cast was placed, along with different multimodal tumor models, in a liver shaped mold, which was subsequently filled with a polymer. After curing, the wax was melted and flushed out of the model, thereby establishing a system of interconnected channels, replicating the major vasculature of the original liver. Thus, a liquid can be circulated through the model in a way that closely mimics the natural blood flow.

Results

Both the tumor models, i.e., the metastatic tumors, hepatocellular carcinoma and benign cyst, and the vessels inside the liver model, were clearly visualized by all the three imaging modalities: CT, MR and ultrasound. Doppler ultrasound images of the vessels proved the blood flow functionality of the phantom.

Conclusion

By a two-step casting procedure, we produced a multimodal liver phantom, with open vascular channels, and tumor models, that is the next best thing to practicing imaging and guidance procedures in animals or humans. The technique is in principle applicable to any organ of the body.